他汀类药物的副作用除了停药还能作些什么？.pdf

他汀类药物的副作用除了停药还能作些什么？Adverse effects of statins:Strategies beyond discontinuation中国医学科学院 阜外心血管病医院Fu Wai Cardiovascular Hospital,CAMS Disclosure（讲前声明）No any interest was involved in this Lecture冠心病:发展中国家的严峻挑战CHD:Severe challenge in developing countries口 WH02008年报告：心血管病死亡占全球死亡31%,排名第一（传染病29%）17,00万/年死于动脉粥样硬化性疾病 80%分布在低中等收入国家包括中国 我国每年死于冠心病的人数达250万5项经典他汀类里程碑临床试验Landmark studies of statin-related clinical trialsLDL-C降低15.9/13.222.62.8TexCAPS n=6,605 TC 5.7 mmol/lWOS n=6,595 TC 7.0 mmol/l冠心病+胆固醇高35%25%冠心病+9胆固醇不高无冠心病 胆固醇高卜无冠心病4 胆固醇不高32%26%23%事件减少34%24%23%31%35%奠定了他汀类药物的临床广泛与强化应用的基础优化药物治疗是现代冠心病治疗主流Current strategies of medication therapy for coronary heart disease药物危险性减少(%)5年事件发生率(%)无药物治疗020.0阿司匹林2515.0B受体阻滞剂2511.3AC日258.4他汀类药物305.9同时使用上述4种药物，可使总的死亡危险性减少70%5年中，每治疗7位患者，便可减少1例主要心血管事件Yusuf et al.Rev Cardiovasc Med.2003;4(suppl 3):537-4 6.他汀促进强化调脂与靶目标概念诞生Target of lower-density cholesterol following lipid-lowering therapy危险等级彳氐危：（10年危险性 24 0 LDL-C160TC200LDL-C130TC 1 60 LDL-C 100TC120LDL-O8 0治疗开始(mg)TC270 LDL-C190TC 24 0 LDL-C 160TC 1 60 LDL-C 100TC160LDL-C8 0目标值(mg)TC24 0LDL-C160TC200LDL-C130TC160LDL-C100TC120LDL-C8 0中国成人血脂异常防治指南委员会,中华心血管病杂志2007;35:390-413.Safety Issue of Statin Therapyan long-term important issueJournal at the Auxiican College of Cardiok*0 3202 by fhe Amwicin Cclkyjc of Caudiolo空 Foundurjou and the Amerkan Heut AMoeution Piihlitlxd ly Elsevier Science I DC2002ACC/AHAHLBI CLI NI CAL ADVI SORY ON STATI NSACC/AHA/NHLBI Clinical Advisor y on th e Use and Sate tv of Statins2006Final Conclusions and Recommendations of th e National Lipid Association Statin Safety Assessment Task For ceJames M.McKenney.Ph ar mD/*Michael H.Davidson.MD,1,Ter r y A.Jacobson.MD?and John R.Guyton.MDdWRITING COMMITTEE MEMBERSRI CHARD C.PASTERNAK,MD,FACC,FAHA SI DNEY C.SMI TH Jr,MD,FACC,FAHA C.NOEL BAI REY-MERZ,MD,FACCSCOTT M.GRUNDY,MD.PhUJAMES 1.CLEEMAN,MD CLAUDE LENFANT,MD,FA5TABLE OF CONTENTSI ncidence of Adver se Events.S69Mech anism of Myopath y.570Bdselme Measur emeots-.一一一一一570Monitor ing tor Adsr fse Reacuom and Adjusting Th er apy 571AsTOptcmatK Patients With CK Ekva口0n.S71I ncr eased Risk States tor SutJ D-I nduced Myopath y-571Clinical Pr ecautions 一一一一371and Blood I nstitute(ACC/AHAN soty is intended co summar ize for pH under standing of statin use,pr ovide updated r ecommendations H of statins,including cautions,contr.monitor ing for statin ther apy.Ie pqj age r he appr opr iate use of statins,.potential in pr oper ly selected pati.with established cor onan,h ear t di辽 at high r isk for developing CHDi myopathy infor mation compiled by fr om clinical tr ials,and summar ies11 leased r epor t of r h e Adult Tftatnienfl the National Ch olester ol Education2I NTRODUCTI ON I n th e liter atur e,th e gener al ter mir flh jpThis art icle sumnKiri/csIhc final conclusions of t he Nat ional lipid AsMKiafion(NLA)St at in Safet y Task Force,based on a review and independent research of New Drug Applicat ion(NDA)informat ion.US Food and Drug Administ rat ion(FDA)Adverse Event Report ing Syst em(APRS)dat a,cohort and cliniud t rial result s,and analysis ut administ rat ive claims dat akbc informat ion and t he assessment of it s 4 Expert Panels,which focused nn issues of st at in safet y wit h reg ard t o liver,musde.renal,and neurolog ic syst ems.Pract ical g uidance in t he form of recommendat ions Io healt h profcKsionals who manag e t he coronary art ery disease risk of pat ient s wit h Mat in t herapv is provided.2006 Elsevier Inc.All rig ht s reserved.(Am J Cardiol 2006:Q7|siippl|:89C-Q4()In t he sect ions t hat follow,t he Nat ional Lipid Associat ion NLA|S(a(in Safet y Task Force draws from t he ext ensive evidence so superbly pivsent ed and analyzed by t he scient ist s and expert s who aut hored(he preceding art icles In t his supplenienl.The Task Force herein offers whal It believes t o he a summary ol final conclusions t hat can he made based on t his evidence and provides piaciical g uidance in t he form of recommendahons t o healt h pt oiessinals who nunag e t he coronary art eiy disease risk of pat ient s wit h st at in t herapy*The Liver and St alin Salet)-Wc IALT and/or AST 3 t imes t he ULN is mosl oft en t ransient and will resolve spont aneously In 70%of cases even if t he skuin and dose are coniinued unchang ed 工To more accurat ely ident ify palieni wit h a persisleni liver t est abnormalit y,some inveslig at ors have adopt ed a more rig orous definit ion,eg.ALT or AST 3 t imes t he ULN on 2 consecut ive occasions When t his det lnihon is applied.t he number of paiient s wit h a sig nificant elevat ion drops from 300 per 100.000 person-years t o 110 per 100.000 person-years?Reduct ion in t he dose or wit hdrawal of t he st at in reg ukirly result s in a ret urn ot t he elevat ed enzyme levels lo normal wit houl adverse sequelae.外心血管病度眄竽1金他汀应用需要格外关注药物的安全性Special attention on safety issue of statin therapy药物间相互作用肌毒性与肝毒性临床要点他汀类药物的副作用机制尚不十分清楚 严重不良反应绝对停用(Discontinucition)他汀类药物相互作用的可能风险Possible risk of drugs when co-administration with statin口合并高血压，同时服用钙离子拮抗剂，辛伐他汀邛可 托伐他汀慎重使用（定期监测CK）口合并房颤，辛伐他汀,阿托伐他汀应在监测CK下慎用口心衰患者，辛伐他汀，阿托伐他汀应在定期监测CK及 地高辛浓度下慎重使用 PCI术后，联合使用氯毗格雷，辛伐他汀，阿托伐他汀 应在定期监测CK下慎重使用他汀应尽量避免与烟酸类和贝特类药物合用他汀类药物应用的肌毒性问题Statin-associated myopathy:an important issue口肌病：他汀类药物最严重的不良反应 Mechanism:G emonic variation口表现：肌痛或肌无力，伴有CK升高至正常上 限10倍以上，也可有发热和全身不适症状口发生率：大约是0.1%,且与剂量有关 口危害：肌病未能及时被发现，仍旧继续用药,则可能导致横纹肌溶解和急性肾功能衰竭他汀类药物肌毒性的临床认知Statin-related toxic myopathy:clinical recognitionTh e clinician sh ould suspect a toxic myopath y wh en a patient without a pre-exis ting muscle disease develops myalgia,fatigue,weakness or myoglobinuria,tempor ally connected to th e administr ation of a statin or exposur e to a myotoxic substance.Dalakas MC.J Neurol Neurosurg Psychiat ry 2009;80:832-838.例心血管他汀类药物肌肉症状的基本定义Definition of statin-associated myopathy肌毒性表现基本定义肌病肌肉的任何疾病肌痛肌肉疼痛或疲软不伴CK升局肌炎有肌肉症状伴CK升高肌溶解有肌肉症状伴CK显著升高（以超过正 常高限ULN 1。倍以上并伴肌酎升高 为典型）1.Pasternak R et al.Circulation 2002;106:1024-282.Ucar M et al.Drug Saf 2000;22:4 4 1-57澳大利亚报道他汀类药物致肌病的危险因素Risk factors of statin-related myopathy in Australia通过CYP3A4代谢而抑制他 汀类药物代谢的物质通过其他作用方式抑制他汀 类药物代谢的药物疾病状态高龄环抱素、钙离子拮抗剂，大环内 酯类抗生素、毗咯抗真菌类药物、蛋白酶抑制剂、葡萄柚果汁吉非贝齐糖尿病、甲状腺功能减退、肾和肝脏疾病 7 0岁大剂量服用他汀类药物Australian Adverse Drug Reactions Bulletin.2004 Feb;23(1)他汀类副作用：除了停药还能作些什么?Adverse effects of statins:Strategies beyond discontinuation 减量与间断应用(r educe dose and nondaily dosing r egimes)他汀类药物之间的转换应用(statinswitch ing)非他汀降脂药物的替换应用(nonstatin alter natives)他汀与降脂药物联合应用(combination of ow-dose statin and oth er s)保护性药物的联合应用(coenzymeQI0 supplementation)外心血管他汀类副作用：除了停药还能作些什么?Adverse effects of statins:Strategies beyond discontinuation减量与间断应用Reduce dose and nondaily dosing regimes长期治疗是他汀获益的必要条件Benefits of statin therapy derived from long-term administration58项他汀临床试验荟萃分析的结果（治疗组76,359;安慰剂71,962）试验时间危险性降低（）第6年以后36(26-4 5)Law MR.Br Med J 2003;326:14 23他汀突然撤除会增加心血管事件Increased mortality after withdrawing a statin therapy8 6 4 41 41 41(一工*-otOE力2 w 8 6St at ins discont inuedNo st at insSt at in cont inuedWithdrawal of Statins:增加ACS患者心血管事件发生可能机制之一炎症因子反弹?10 15 20 25 3030-day follow-up penodCirculation 2002；105：1446-1542.Li J-J,et al.Med Hypo 2006;66:478.他汀撤除事件增加的可能机制：炎症“反弹，Increased mortality after withdrawing a statin therapyTime Median CRP(mg/dl)Mean CRP(mg/dl)IL-6(pg/dl)Baseline0.150.300.108.4 0.66 weeks0.100.220.096.7 0.4WithdrawalDay 10.100.210.096.8 0.5Day 30.140.270.147.7 0.6Day 70.160.310.158.7 0.8Li J-J,et al.Clin Chim Acta 2006;366:273-279.AtoZ研究中不良事件发生率与剂量关系Rate of adverse effects occurred in A to Z study不良反应类型 辛伐他汀4 0或8 0mg/日安慰剂+辛伐他汀20mg/日AST或ALT3倍ULN 19/2132(0.9)8/2068(0.4)横纹肌溶解#3/2230(0.1)0/2230(0)肌病 9/2263(0.4)1/2230(0.04)因肌肉方面不良反应而停药 41/2263(1.8)34/2230(1.5)de Lemos JA,et al.JAMA 2004;292:1307-1316.TNT研究不良事件发生率与剂量关系Safety issue of high-dose statin administration in TNT study不良反应类型阿托伐他汀10mg 阿托伐他汀8 0mg P值(n=5,006)(n=4,995)和治疗相关的副反应 289(5.8)和治疗相关的肌痛 234(4.7)肌溶解*3(0.06)肝酶升高大于三倍 9(0.2)406(8.1)0.001241(4.8)0.722(0.04)60(1.2)65 yrs)with Ml接受二种降压方案治XZK or或安慰 剂治疗，随访4.5年口结果与结论：XZK(含洛伐他汀10mg明显 降低老年心梗后高血压患者的心血管事件Li J-J,Lu Z-L,et al.J Clin Pharmacol 2009;4 7:94 7-956.例心血管他汀类副作用：除了停药还能作些什么?Adverse effects of statins:Strategies beyond discontinuation他汀类药物之间的转换应用Statin switchingStatin switching:a case report Cqs rpo什：1 59-year-old women withh q 什 trcinsplcintcition 4 y cirs rcilir.Pravastatin 20mg/d for 4 years After switching from pravastatin to simvastatin,she developed svr muscular wciknss until rpcit hmodicilysisSochman J,Podzimkova M.Int J Cardiol 2005;99:145-146.Statin switching:basic mechanismDrug interactions between statin and other medications氟伐他汀较危险的途径辛伐他汀心血管药物（钙离子拮抗剂,氯此格雷，贝特类，烟酸，地高辛，华法令）抗菌药（克拉霉素、红霉素）抗哮喘药物（茶碱）免疫抑制剂（环抱素）胃肠道药物（奥美拉喳）Ballantyne C et al.Arch Intern Med 2003;163:553-564Corsini A.Cardio vase Drugs Ther 2003;17:257-277Statin switching:basic mechanismCell-selective action of Water-loving and water-hating statin西立伐他汀辛伐他汀氟伐他汀阿托伐他汀相对亲脂性*log D at pH 7.4Buckett et al.z(2000);McTaggart et al.,(2001)亲水的磺酸基团”.相对亲水性*瑞舒伐他汀普伐他汀普伐他汀在肝脏高度选择性分布High-degree selective action in liver following pravastatin administration 静注C14标记美百乐镇0及ML-236B后大鼠全身放射显影照片Arai M,et al.Annu Rep Sankyo Res Lab 198 8;l:4 0.PRIMO研究:他汀类药物剂量和肌肉症状风险Statin dosing and statin-relating myopathy in PRIMO studyBruckert B et al.Cardiovasc Drugs Ther 2006;19:403-414.他汀类药物剂量出现肌肉症危险比十95%CIP值*(N=7924)状的比例普伐他汀40 mg/天10.9%1阿托伐他汀40-80 mg/天14.9%1.281.02-1.600.035辛伐他汀40-80 mg/天18.2%1.781.39-2.290.0001氟伐他汀80 mg/天5.1%0.330.26-0.420.0001FDA报道他汀发生肌毒性事件Statin-related toxic myopathy:Are all statins same?他汀类氟伐普伐洛伐阿托伐辛伐西立伐他汀他汀他汀他汀他汀他汀横纹肌溶解0.61.21.21.23.688.7肌病0.61.44.20.51.66.5肌炎0.21.03.90.61.311.5肌痛2.75.816.48.07.546.3FDA report data on file例心血管他汀类副作用：除了停药还能作些什么?Adverse effects of statins:Strategies beyond discontinuation非他汀降脂药物的替换应用Nonstatin alternatives非他汀降脂药物替换应用的临床选择Clinical selection of nonstatin lipid-lowering drugs口烟酸 多廿烷醇 Red yeast rice（血脂康）co-3-脂肪酸口依折麦布烟酸类调脂药物的作用特点与应用Clinical features and application of Niacin-derived drugs B族维生素(vitamin B3),大剂量有降脂作用；适用高TG 血症，低HDL-C血症或以TG升高为主混合型高脂血症口速释剂烟酸不良反应明显，现已不用。缓释型烟酸不 良反应明显减轻，较易耐受临床试验 CDP,CLAS-I,FATS,HATS,ARBI TER2等证实，烟酸降低主要冠脉事件减少总死亡率口常见不良反应：颜面潮红、高血糖、高尿酸(或痛风)、上消化道不适等。绝对禁忌证为慢性肝病和严重痛风；相对禁忌证为溃疡病、肝毒性和高尿酸血症Study on extended niacin application Design:Randomized,double-blind,placebo controlled multicenter,24-week trial Drug:Combination of Niacin 2000mg/laropiprant 4 0mg Results:LDL-C-18%Incidence and intensity of flushing were significantly reduced compared with Niacin 2000mg alone.Conclusion:Combination of Niacin/laropiprant was generally well tolerated by adults with dyslipidemia.Perry CM.Drugs 2009;69:1665-1679.多廿烷醇调脂治疗临床应用文献汇总作用机制：通过腺昔酸激酶选择性阻断HMG-CoA还原 酶的活性（他汀完全阻断HMG-CoA合成酶）口调脂作用：10mg/d:LDL-C-17%;HDL-C+5%20mg/d:LDL-C-24%;HDL-C+18%证据：1）肝酶异常者（ALA45U/L）应用无恶化现象2）迄今无肌病及肌溶解报道J Geront ol Med Sci 2001;13:1-9;Curr Ther Res 1996;57:118-127.Red yeast rice（红曲）for dislipidemia in a statin-intolerant patients:a randomize trial Design（设计）:Randomized,controlled trial Patients（患者）：62名他汀肌病停药者 Therapy（治 疗）：Rid yeast rice 18 00mg（Sylvan bioproducts,Kittanning,Pennsylvania）or placebo（n=31 respectively）Bid口 Follow-up（随访）:24 weeks,primary outcome:LDL-C;secondary outcome:TC,HDL-C,TG,Liver enzyme,CK,weight,口 Results（结果）：LDL-C减少：l.llmmol/L vs 0.28 mmol/L at 12 wks,0.93 mmol/L vs 0.39 mmol/L at 24 wks Conclusion（结论）:Red yeast rice may be a treatment option for dislipidemic patients who cannot tolerate statin therapyBecher DJ,et al.Ann Intern Med 2009;150:8 30-8 39.Omega-3-fatty acids（3-3-脂肪酸）：an cardiovascular agent Lipid-r elated effects:dose-dependently r educe blood TG Pleiotr opic effects:favor able effects on inflammator y pr ocess,endoth elial dysfunction,platelet aggr egation and ar r h yth mogenesisO Administr ation:used alone or used in combination with statin MACE:need fur th er study and mor e evidenceDimitrow PP,et al.Mini Rev Med Chem 2009;9:1030-1039.他汀类副作用：除了停药还能作些什么?Adverse effects of statins:Strategies beyond discontinuation小剂量他汀与降脂药物联合应用Combination of low-dose statin and othr lipid-lowring drugs小剂量他汀与其它调脂药物联合应用Combination of low-dose statin and other lipid-lowering drugs Bile acid sequestr ants（多价螯合剂）（Ch olestyr amine,colestipol,colesevelam）Ezetimibe Niacin Plant ster ols（植物固醇）Fibr ate（fenofibr ate,bezafibr ate,gemfibr ozil）Omega-3-fatty acids（co-3-脂肪酸）小剂量他汀与其它调脂药物联合应用Combination of low-dose statin and other lipid-lowering drugs口目的：维持达标水平，降低不良反应与事件 口原则：小剂量他汀与另外一种降脂药物组成It has to stated that for most of these combination therapies data on cardiovascular outcomes are still lacking.Fundam Clin Pharmacol 2009;14:8 8-94.外心血管:临床上可供选择的联合治疗模式Models of lipid-lowering combination therapy小剂量他汀类治疗LDL未达到目标I HDL未达到目标Ltg未达到目标*加用烟酸*加用贝特类 加用伊折麦布*加用烟酸*加用贝特类药物*加用烟酸*加用贝特类药物 加用鱼油*=增加肌病危险性Grundy S,Am J Cardiol 2002;90:1135-38 依折麦布辛伐他汀:显著降低LDLCMore reduction of LDL-C levels following EZE+Simvastatin%x y 转fr依 10 mg+0-10-20-30-40-50-60辛伐他汀10 mg 10 mg 20 mg 40 mg 80 mg辛伐他汀*联合治疗与单用他汀比较p=O OOI va oorr9K3nllr(Q yf 5IKVAp053n=77 n=83Zhao X et al.J Am Coll Cardiol,2002;39:24 2A;1130-73.他汀类副作用：除了停药还能作些什么?Adverse effects of statins:Strategies beyond discontinuation非他汀类降脂药物联合应用Combination of non-statin lipid-lowering drugs非他汀降脂药物联合应用的临床方向Novel nonstatin strategies to lower LDL-C口 Niacin-resin or fibrate-niacin Extended-release niacin/hropipran Squalene synth ase inh ibitor（角 鲨 烯合成 酶抑制剂）口 Micr osomal tr iglycer ide tr ansfer pr otein inh ibitor（微粒体甘油三脂转运蛋白抑制剂）antisense apolipopr otein B（反义载脂蛋白B）Curr Atheroscler Rep 2009;11:67-70.Extended niacin/laropiprant application Design:Randomized,double-blind,placebo controlled multicenter,24-week trial Drug:Combination of Niacin 2000mg/laropiprant 4 0mg Results:LDL-C-18%Incidence and intensity of flushing were significantly reduced compared with Niacin 2000mg alone.Conclusion:Combination of Niacin/laropiprant was generally well tolerated by adults with dyslipidemia.Perry CM.Drugs 2009;69:1665-1679.Raising HDL-C with niacin and fibrates:a comparative review Design:A h ead-to-h ead compar ative studyO Dr ug:Combination of Niacin 2,000mg/Gemfibr ozil1,200mg compar ed with Niacin or Fib r ate tr ial alone indexes:TC/HDL-C,Lp(a)and fibr inogen Conclusion:Combination th er apies of Niacin plus a r esin ar e effective,well toler ated,and safe.Sprecher D,Am J Cardiol 2001;8 6(suppl 1):4 6-50.例心血管他汀类副作用：除了停药还能作些什么?Adverse effects of statins:Strategies beyond discontinuation保护性药物的联合应用Coenzyme Q10 supplementation保护性药物联合应用的临床证据Clinical application of statin with preventive drugs BrJ Clin Pharmacol 1996;4 2:333-337.Ann Intern Med 2002;137:58 1-58 5.Arch of Neurol 2004;61:8 8 9-8 92.EurJ Clin Invest.2005;35:251-258.Am J Cardiol 2004;94:1306-1310.O G eorgian Medical News 2005(1):20-24.辅酶Q10与他汀类药物的机制关系Possible Mechanism of Co-Q10 and statins他汀类药物与对辅酶Q10水平影响Decreased levels of Co-Q10 in pat ient s t reat ed wit h st at in辅酶。水车1 8 6 4 2 0 slo.s 640名接受他汀类药物治疗，20名接受国 类药物，20名没有药物治疗，20名健康;照者入住及试验一周后采集血样尸0.05 vs健康对照组0.91h 0-95h0.75e0.96Tr 辛伐他汀(n=40)贝特类(n=20)未治疗患者(n=20)健康对照者(n=20)贝他汀性肌病与线粒体功能异常St at in-induced myopat hy is associat ed wit h mit ochondrion dysfunct ionAnn Intern Med.200